Glucagon-like peptide-1 receptor agonist exendin 4 ameliorates diabetes-associated vascular calcification by regulating mitophagy through the AMPK signaling pathway.

BACKGROUND: Vascular calcification (VC) is a complication in diabetes mellitus (DM) patients. Osteogenic phenotype switching of vascular smooth muscle cells (VSMCs) plays a critical role in diabetes-related VC. Mitophagy can inhibit phenotype switching in VSMCs. This study aimed to investigate the role of the glucagon-like peptide-1 receptor (GLP-1R) agonist exendin 4 (EX4) in mitophagy-induced phenotype switching. MATERIALS AND METHODS: The status of VC in T2DM mice was monitored using Von Kossa and Alizarin Red S (ARS) staining in mouse aortic tissue. Human aortic smooth muscle cells were cultured in high glucose (HG) and ß-glycerophosphate (ß-GP) conditioned medium. Accumulation of LC3B and p62 was detected in the mitochondrial fraction. The effect of EX4 in vitro and in vivo was investigated by knocking down AMPKα1. RESULTS: In diabetic VC mice, EX4 decreased the percentage of von Kossa/ARS positive area. EX4 inhibited osteogenic differentiation of HG/ß-GP-induced VSMCs. In HG/ß-GP-induced VSMCs, the number of mitophagosomes was increased, whereas the addition of EX4 restored mitochondrial function, increased the number of mitophagosome-lysosome fusions, and reduced p62 in mitochondrial frictions. EX4 increased the phosphorylation of AMPKα (Thr172) and ULK1 (Ser555) in HG/ß-GP-induced VSMCs. After knockdown of AMPKα1, ULK1 could not be activated by EX4. The accumulation of LC3B and p62 could not be reduced after AMPKα1 knockdown. Knockdown of AMPKα1 negated the therapeutic effects of EX4 on VC of diabetic mice. CONCLUSION: EX4 could promote mitophagy by activating the AMPK signaling pathway, attenuate insufficient mitophagy, and thus inhibit the osteogenic phenotype switching of VSMCs.

CDKN2B-AS1 mediates proliferation and migration of vascular smooth muscle cells induced by insulin.

Excessive proliferation and migration of vascular smooth muscle cells (VSMCs) contribute to the intimal hyperplasia in type 2 diabetes mellitus (T2DM) patients after percutaneous coronary intervention. We aimed to investigate the role of lncRNA cyclin-dependent kinase inhibitor 2B antisense RNA 1 (CDKN2B-AS1) in VSMC proliferation and migration, as well as the underlying mechanism. T2DM model mice with carotid balloon injury were used in vivo and mouse aortic vascular smooth muscle cells (MOVAS) stimulated by insulin were used in vitro to assess the role of CDKN2B-AS1 in VSMC proliferation and migration following vascular injury in T2DM state. To investigate cell viability and migration, MTT assay and Transwell assay were conducted. To elucidate the underlying molecular mechanisms, the methylation-specific polymerase chain reaction, RNA immunoprecipitation, RNA-pull down, co-immunoprecipitation, and chromatin immunoprecipitation were performed. In vivo, CDKN2B-AS1 was up-regulated in common carotid artery tissues. In vitro, insulin treatment increased CDKN2B-AS1 level, enhanced MOVAS cell proliferation and migration, while the promoting effect was reversed by CDKN2B-AS1 knockdown. CDKN2B-AS1 forms a complex with enhancer of zeste homolog 2 (EZH2) and DNA methyltransferase (cytosine-5) 1 (DNMT1) to regulate smooth muscle 22 alpha (SM22α) methylation levels. In insulin-stimulated cells, SM22α knockdown abrogated the inhibitory effect of CDKN2B-AS1 knockdown on cell viability and migration. Injection of lentivirus-sh-CDKN2B-AS1 relieved intimal hyperplasia in T2DM mice with carotid balloon injury. Up-regulation of CDKN2B-AS1 induced by insulin promotes cell proliferation and migration by targeting SM22α through forming a complex with EZH2 and DNMT1, thereby aggravating the intimal hyperplasia after vascular injury in T2DM.

M6A methylation-mediated elevation of SM22α inhibits the proliferation and migration of vascular smooth muscle cells and ameliorates intimal hyperplasia in type 2 diabetes mellitus.

Abnormal proliferation of vascular smooth muscle cells (VSMCs) induced by insulin resistance facilitates intimal hyperplasia of type 2 diabetes mellitus (T2DM) and N6-methyladenosine (m6A) methylation modification mediates the VSMC proliferation. This study aimed to reveal the m6A methylation modification regulatory mechanism. In this study, m6A demethylase FTO was elevated in insulin-treated VSMCs and T2DM mice with intimal injury. Functionally, FTO knockdown elevated m6A methylation level and further restrained VSMC proliferation and migration induced by insulin. Mechanistically, FTO knockdown elevated Smooth muscle 22 alpha (SM22α) expression and m6A-binding protein IGF2BP2 enhanced SM22α mRNA stability by recognizing and binding to m6A methylation modified mRNA. In vivo studies confirmed that the elevated m6A modification level of SM22α mRNA mitigated intimal hyperplasia in T2DM mice. Conclusively, m6A methylation-mediated elevation of SM22α restrained VSMC proliferation and migration and ameliorated intimal hyperplasia in T2DM.

LncRNA SNHG15 relieves hyperglycemia-induced endothelial dysfunction via increased ubiquitination of thioredoxin-interacting protein.

Numerous studies have revealed that hyperglycemia is a pivotal driver of diabetic vascular complications. However, the mechanisms of hyperglycemia-induced endothelial dysfunction in diabetes remain incompletely understood. This study aims to expound on the underlying mechanism of the endothelial dysfunction induced by hyperglycemia from the perspective of long non-coding RNAs (lncRNA). In this study, a downregulation of SNHG15 was observed in the ischemic hind limb of diabetic mice and high glucose (HG)-treated HUVECs. Functionally, the overexpression of SNHG15 promoted cell proliferation, migration, and tube formation, and suppressed cell apoptosis in HG-treated HUVECs. Mechanistically, SNHG15 reduced thioredoxin-interacting protein (TXNIP) expression by enhancing ITCH-mediated ubiquitination of TXNIP. TXNIP overexpression abrogated the protective effect of lncRNA SNHG15 overexpression on HG-induced endothelial dysfunction. The following experiment further confirmed that SNHG15 overexpression promoted angiogenesis of the ischemic hind limb in diabetic mice. In conclusion, SNHG15 is a novel protector for hyperglycemia-induced endothelial dysfunction via decreasing TXNIP expression.

Experimental Analysis of the Quality of Needle-Assisted Fenestration in Aortic Stent-Grafts and the Differences Between Gradual and Rapid Balloon Dilation.

Purpose: To report the findings of an in vitro experiment to evaluate the quality of needle fenestrations dilated by different size balloons in various stent-grafts and to investigate the differences between gradual and rapid dilation. Materials and Methods: Fenestrations were made using an 18-G needle in 5 different polyester or expanded polytetrafluoroethylene (ePTFE) stent-grafts: Relay, Valiant, Hercules, TAG, and Ankura. Each stent-graft received 2 groups of fenestrations: one was followed by gradual sequential dilation (4-, 6-, 8-, and 10-mm balloons) and the other by rapid dilation (4- and 10-mm balloons). The pressure was increased to 10 atmospheres or until the balloon was fully inflated with no waist. Quantitative and qualitative evaluations, including fenestration diameter, area, shape, and margins were conducted using light microscopy and scanning electron microscopy. Results: Relay had the strongest resistance to dilation and Ankura the slightest. The maximum length and area of holes expanded as the balloon diameter increased. The fenestrations in polyester devices were mostly elliptical or slit-like, with limited tears but extensive fibers visible in the margin, while ePTFE stent-grafts showed larger fenestration areas with clearer margins. Ankura showed the best quality of fenestrations, which were always circular or square without fabric tears, while the holes in the TAG were square or elliptical but sometimes had a slit after large balloon dilation (≥6 mm). The Relay, Valiant, Hercules, and Ankura devices showed no difference in maximum diameter, fenestration area, or scores of shape and margin (p>0.05). Rapid dilation in the TAG increased the rate of uncontrolled fabric tear, resulting in a larger final diameter (12.90 vs 10.82 mm, p=0.047), smaller area (30.46 vs 41.09 mm2, p=0.028), worse shape (0.75 vs 1.20, p=0.268), and worse margin (0.40 vs 1.00, p=0.174). Though the decreased fenestration shape and margin scores did not reach statistical significance, the trend for decline was more obvious than with the other devices. Conclusion: Materials and structures of the stent-grafts determine the quality of fenestrations dilated by different size balloons. The use of sequential vs rapid balloon dilation is also crucial for fashioning high-quality fenestrations and should be selected judiciously.

Long-term Results of Thoracic Endovascular Aortic Repair for Type B Aortic Dissection and Risk Factors for Survival.

Purpose: To compare characteristics of acute, subacute, and chronic type B aortic dissection and their influence on long-term results of thoracic endovascular aortic repair (TEVAR). Materials and Methods: In a single-center, retrospective cohort study, 314 patients (median age 52 years; 244 men) with acute (n=165), subacute (n=115), or chronic (n=34) type B aortic dissection underwent TEVAR between January 2009 and December 2013. Patient demographics, risk factors, and imaging characteristics were compared among the groups. Univariable and multivariable Cox regression analyses were performed to identify any factors influencing survival. Results: The acute and subacute patients exhibited more complications at presentation than chronic patients. However, the chronic patients exhibited more aneurysmal dilatation (p<0.001) and true lumen collapse (p<0.001). Over a mean follow-up of 68.1±22.9 months (range 2-108), subacute patients showed a lower reintervention rate (3.6% vs 12.1% vs 12.1%, p=0.045), a lower major complication rate (14.4% vs 33.1% vs 27.3%, p=0.002), and better cumulative overall survival (p=0.03) than the acute and chronic groups, respectively. Furthermore, acute patients developed more stent-graft-induced distal erosion (p=0.017) and retrograde type A dissection (RTAD) (p=0.036), whereas chronic patients had less aortic remodeling in the stented segment (p<0.001), distal thoracic aorta (p<0.001), and abdominal aorta (p=0.047). Finally, multivariable analysis demonstrated age >52 years, visceral malperfusion, and RTAD as independent factors influencing overall survival; aneurysmal dilatation, rupture/impending rupture, and RTAD were independent factors influencing aorta-specific survival. Conclusion: Acute and subacute patients had increased risks of rupture and complications at presentation, whereas chronic patients had increased risks for aneurysmal dilatation. From a long-term perspective, the subacute phase might be an optimal time for TEVAR in cases of type B aortic dissection that do not need emergent interventions. The risk factors influencing survival should be identified, carefully managed, and possibly prevented.

Favourable Outcomes of Endovascular Total Aortic Arch Repair Via Needle Based In Situ Fenestration at a Mean Follow-Up of 5.4 Months.

OBJECTIVES: Endovascular repair of aortic arch pathologies remains challenging. Recently, needle based in situ fenestration (ISF) has shown great potential in endovascular total aortic arch repair (ETAAR). This study aimed to evaluate the feasibility, effectiveness, and safety of ETAAR via needle based ISF, and to present initial experience with this technique. DESIGN AND METHODS: Patients who met the inclusion criteria were enrolled in this prospective study. The supra-arch branches were manually punctured in a retrograde manner using liver biopsy needles (18 gauge/30 cm) in the left common carotid artery (LCCA) and brachiocephalic trunk (BCT), and endo-puncture system or aspiration biopsy needles (21-gauge) in the left subclavian artery (LSA). All the branches were revascularised with bridge stents. Routine follow-up occurred at 1, 3, 6, and 12 months post surgery. RESULTS: Ten patients with arch pathologies underwent ETAAR. Revascularisation of three branches was successfully performed in eight patients, but attempts to create ISF in LSA were unsuccessful in two patients because of tortuosity and sharp angle. The time taken to establish ISF in LCCA and BCT was 100.4s and 489.6s, respectively. Bilateral regional cerebral oxygen saturation (RCOS) decreased after the arch endograft deployment (both, p < .001) and recovered to the pre-operative level once both carotid arteries were reconstructed (left, p = .0856; right, p = .6). The right RCOS was higher with the beneficial effect of extracorporeal circulation (after cTAGs deployment, p < .001; after LCCA revascularised, p = .0148) during the ischaemic period. In one case, the left iliac artery ruptured, but no ISF related or neurological complications occurred. An early follow-up (mean 5.44 months) CTA and ultrasound confirmed patency of all the branch grafts without any endoleak or migration CONCLUSIONS: This study demonstrated that ETAAR via needle based ISF, making full use of off the shelf devices and techniques, can be successfully performed in aortic arch pathologies with a favourable early outcome.

Determination of Risk Factors and Establishment of a Prediction Model for Immediate Technical Failure during Endovascular Treatment of Femoropopliteal Occlusive Disease.

BACKGROUND: For long femoropopliteal occlusive lesions, the immediate technical failure (ITF) of endovascular treatment (EVT) is relatively high. Therefore, this study aims to reveal risk factors and establish a prediction model of ITF of EVT in femoropopliteal occlusive disease (FPOD) patients based on preoperative clinical date that may be helpful to the clinical procedures. METHODS: A retrospective analysis of 1,563 FPOD patients who underwent above-the-knee EVT was undertaken. Univariate analysis with chi-squared test was used to screen risk factors from preoperative clinical data. Multivariable analysis with logistic regression was used to generate a model for predicting the ITF rate of EVT, which was evaluated through the receiver operating characteristic curve and another independent cohort of 242 FPOD patients. RESULTS: Risk factors for ITF during EVT in FPOD included age (>80 years, X1), the absence of diabetes mellitus (X2), low-density lipoprotein (>160 mg/dL, X3), lesion calcification (X4), lesion length (>20 cm, X5), ostial occlusion of superficial femoral artery (SFA) (X6), and SFA lesion involving the popliteal artery (X7). A logistic regression model was established based on the equation: -6.504 + 1.236X1 + 0.945X2 + 1.406X3 + 1.136X4 + 1.059X5 + 2.307X6 + 2.194X7. Scores were given to risk factors as follows: X1 (yes = 12, no = 0), X2 (yes = 9, no = 0), X3 (yes = 14, no = 0), X4 (yes = 11, no = 0), X5 (yes = 11, no = 0), X6 (yes = 23, no = 0), and X7 (yes = 22, no = 0). We determined that the optimal comprehensive score for predicting EVT failure was 39, with a sensitivity of 0.847 and a specificity of 0.8. Among these 242 peripheral arterial disease patients, 12 of 14 patients who had failed EVT had a comprehensive score of >39. CONCLUSIONS: We identified a number of risk factors of ITF during the above-the-knee EVT and established a prediction model that may be used for guidance in clinical practice.

Advanced Glycation End-Products Downregulate HoxA9EC through Activation of Nuclear Factor Kappa B by Reciprocal Interaction.

Advanced glycation end-products (AGEs) have been recognized as an important pathophysiological mechanism in endothelial dysfunction during diabetic atherogenesis. Homeobox (Hox) genes have been identified as playing a regulatory role in the adult cardiovascular system. Regulation of HoxA9EC is involved in diabetic endothelial dysfunction, but the mechanism of HoxA9EC regulation has remained undefined. Here, we sought to investigate how HoxA9EC is regulated in AGE-induced endothelial dysfunction and to explore the mechanism involved. We used human umbilical venous endothelial cells (HUVECs) cocultured with AGEs, and examined endothelial nitric oxide synthase (eNOS) activation, nitric oxide (NO) release, cell migration, and the expression of HoxA9EC and nuclear factor kappa B (NF-κB). AGEs suppressed eNOS activation, NO release, and the migration of HUVECs. Knockout of HoxA9EC also reduced eNOS activation, NO release, and the migration of HUVECs, and the enhancement of HoxA9EC improved the function of HUVECs. Furthermore, AGEs downregulated HoxA9EC expression and activated NF-κB, and the depression of HoxA9EC was significantly attenuated by the NF-κB inhibitor. On the other hand, knockout of HoxA9EC activated NF-κB and the enhancement of HoxA9EC suppressed NF-κB activation. In conclusion, AGEs could induce endothelial dysfunction through NF-κB-dependent HoxA9EC downregulation by reciprocal interaction, and the enhancement of HoxA9EC expression could attenuate the impairment.

Induction of autophagy by salidroside through the AMPK-mTOR pathway protects vascular endothelial cells from oxidative stress-induced apoptosis.

Vascular endothelial cells are highly sensitive to oxidative stress, and this is one of the mechanisms by which widespread endothelial dysfunction is induced in most cardiovascular diseases and disorders. However, how these cells can survive in oxidative stress environments remains unclear. Salidroside, a traditional Chinese medicine, has been shown to confer vascular protective effects. We aimed to understand the role of autophagy and its regulatory mechanisms by treating human umbilical vein endothelial cells (HUVECs) with salidroside under oxidative stress. HUVECs were treated with salidroside and exposed to hydrogen peroxide (H2O2). The results indicated that salidroside exerted cytoprotective effects in an H2O2-induced HUVEC injury model and suppressed H2O2-induced apoptosis of HUVECs. Pretreatment with 3-methyladenine (3-MA), an autophagy inhibitor, increased oxidative stress-induced HUVEC apoptosis, while the autophagy activator rapamycin induced anti-apoptosis effects in HUVECs. Salidroside increased autophagy and decreased apoptosis of HUVECs in a dose-dependent manner under oxidative stress. Moreover, 3-MA attenuated salidroside-induced HUVEC autophagy and promoted apoptosis, whereas rapamycin had no additional effects compared with salidroside alone. Salidroside upregulated AMPK phosphorylation but downregulated mTOR phosphorylation under oxidative stress; however, administration of compound C, an AMPK inhibitor, abrogated AMPK phosphorylation and increased mTOR phosphorylation and apoptosis compared with salidroside alone. These results suggest that autophagy is a protective mechanism in HUVECs under oxidative stress and that salidroside might promote autophagy through activation of the AMPK pathway and downregulation of mTOR pathway.

Zinc Finger E-Box Binding Protein 2 (ZEB2) Suppress Apoptosis of Vascular Endothelial Cells Induced by High Glucose Through Mitogen-Activated Protein Kinases (MAPK) Pathway Activation.

BACKGROUND Hyperglycemia has been confirmed to damage endothelial function of vascular and microvascular. The regulation of zinc finger E-box binding protein 2 (ZEB2) on vascular endothelial cells (VECs) is reported rarely. Our study investigates the role of ZEB2 on the apoptosis of VECs induced by high glucose through MAPK pathway. MATERIAL AND METHODS Downregulated and upregulated expression of ZEB2 in human umbilical vein endothelial cells (HUVECs) were performed by plasmids transfection. HUVECs are respectively treated with different concentrations of glucose (5.5 mM, 33 mM). The expression of mRNA and protein were detected by real-time quantified PCR and western blotting. Apoptotic cells were measured by flow cytometry. Proliferation and migration of HUVECs were detected by MTT assay and wound healing assay. RESULTS The apoptosis of HUVECs detected by flow cytometry and western blot revealed that ZEB2 overexpression distinctly suppressed the apoptosis of HUVECs induced by high glucose. ZEB2 overexpression promoted the proliferative and migration activity of HUVECs. Besides, ZEB2 overexpression specifically accelerated the phosphorylation level of JNK, and suppressed the apoptosis and promoted the proliferative of VECs via JNK pathway. CONCLUSIONS ZEB2 suppress apoptosis of VECs induced by high glucose through MAPK pathway activation, which provides a novel insight and therapeutic target for endothelial injury.

Morphologic findings and management strategy of spontaneous isolated dissection of the celiac artery.

OBJECTIVE: We report the morphologic findings and treatment of spontaneous isolated dissection of the celiac artery (SIDCA). METHODS: Twenty-three patients with SIDCA presenting between January 2009 and December 2014 were enrolled in this retrospective study. The demographic data, clinical features, morphologic findings, treatment modalities, and follow-up results of these patients were reviewed. We proposed a morphologic classification for SIDCA similar to that of spontaneous isolated dissection of the superior mesenteric artery. RESULTS: Initially, 11 patients were treated endovascularly, and 12 were treated medically. Four patients treated medically had an aggravation of the dissection and needed endovascular salvage. All patients recovered successfully. None of the patients developed abdominal pain, required reintervention, or died. In the medically treated group, the false lumen was completely thrombosed and absorbed in 4 patients, partially thrombosed in 2, and patent in 2. All stents were patent with the false lumen completely thrombosed and absorbed in the endovascular group. CONCLUSIONS: SIDCA can be treated medically in stable patients but requires intensive follow-up. Endovascular therapy can be applied in high-risk patients with recurrent symptoms, visceral malperfusion, or aneurysm. Open surgery should be considered if endovascular repair is not suitable or has failed. The short-term results of endovascular management are encouraging but further evaluation with long-term follow-up is necessary.

The Use of the Angiosome Concept for Treating Infrapopliteal Critical Limb Ischemia through Interventional Therapy and Determining the Clinical Significance of Collateral Vessels.

BACKGROUND: The purpose of this study was to evaluate the clinical significance of the involvement of collateral vessels in interventional therapy based on the angiosome concept for infrapopliteal critical limb ischemia (CLI). METHODS: We enrolled 486 patients with unilateral infrapopliteal CLI (Rutherford Stage 5 or 6) treated at 2 hospitals from January 2005 to December 2014. Using the angiosome concept, the patients were categorized into 3 groups: the direct revascularization (DR) group, the indirect revascularization through collaterals (IR-tc) group, and the indirect revascularization without collaterals (IR-wc) group. The data from 1 year of follow-up after the initial surgery were analyzed for all 3 groups. RESULTS: During the 1-year follow-up, the unhealed ulcer rate of the IR-wc group was significantly higher than that of the DR group (83.4% vs. 31.7%, P < 0.001) and the IR-tc group (83.4% vs. 34.8%, P < 0.001). Furthermore, the limb salvage rate of the IR-wc group was significantly lower than that of the DR group (70.4% vs. 89.2%, P < 0.001) and the IR-tc group (70.4% vs. 85.4%, P = 0.0013). However, there were no differences in the unhealed ulcer rate or the limb salvage rate between the DR group and the IR-tc group (31.7% vs. 34.8%, P = 0.096 and 89.2% vs. 85.4%, P = 0.2834, respectively). In addition, within the IR-wc group, the unhealed ulcer rate of diabetic patients was higher than that of patients without diabetes (90.0% vs. 74.6%, P = 0.0116), but there was no difference in the limb salvage rate between diabetic and nondiabetic patients. No differences in the unhealed ulcer rate or the limb salvage rate were found between diabetic and nondiabetic patients in the other 2 groups. CONCLUSIONS: Following the angiosome model of perfusion for endovascular therapy, directly revascularizing the feeding artery and indirectly achieving revascularization through collaterals can effectively prompt the healing of ulcers and decrease the amputation rate in patients with infrapopliteal CLI. Collateral vessels play a crucial role in the treatment of ischemic foot.

Dynamin-related protein 1 mediates the therapeutic effect of isoliquiritigenin in diabetic intimal hyperplasia via regulation of mitochondrial fission.

Phenotypic shift of vascular smooth muscle cells (VSMCs) plays a key role in intimal hyperplasia, especially in patients with diabetes mellitus (DM). This study aimed to investigate the role of dynamin-related protein 1 (DRP1) in mitochondrial fission-mediated VSMC phenotypic shift and to clarify whether DRP1 is the therapeutic target of isoliquiritigenin (ISL). Wire injury of carotid artery or platelet-derived growth factor treatment was performed in DM mice or high-glucose cultured human aortic smooth muscle cells (HASMCs), respectively. The effects of DRP1 silencing on DM-induced intimal hyperplasia were investigated both in vivo and in vitro. Phenotypic shift of HASMCs was evaluated by detection of reactive oxygen species (ROS) generation, cell viability, and related protein expressions. The effects of ISL on DM-induced intimal hyperplasia were evaluated both in vivo and in vitro. DRP1 silencing and ISL treatment attenuated DM-induced intimal hyperplasia with reduced ROS generation, cell viability, and VSMC dedifferentiation. The GTPase domain of DRP1 protein played a critical role in mitochondrial fission in DM-induced VSMC phenotypic shift. Cellular experiments showed that ISL inhibited mitochondrial fission and reduced the GTPase activity of DRP1, which was achieved by the directly binding to K216 of the DRP1 GTPase domain. ISL attenuated mouse intimal hyperplasia by reducing GTPase activity of DRP1 and inhibiting mitochondrial fission in vivo. In conclusion, increased GTPase activity of DRP1 aggregated DM-induced intimal hyperplasia by increasing mitochondrial fission-mediated VSMC phenotypic shift. ISL attenuated mouse intimal hyperplasia by reducing DRP1 GTPase activity and inhibiting mitochondrial fission of VSMCs.

A 10-year experience of leiomyosarcoma of the inferior vena cava.

OBJECTIVES: Leiomyosarcoma of the inferior vena cava (IVC) is rare. The study reviewed patients with IVC leiomyosarcoma in our hospital in the past ten years. METHODS: Twenty patients diagnosed with IVC leiomyosarcoma between October 2010 and October 2020 were enrolled. Their clinical manifestations, treatments, and follow-up results were analyzed. RESULTS: The sarcoma was located in the lower IVC segment in six patients, with 13 in the middle and one in the upper IVC segment. Eighteen patients underwent R0 resection. After resection, 16 patients (80%) had primary repair of the IVC, while four patients underwent ligation. During a mean follow-up of 37.7 months, seven patients died due to tumor metastasis, four patients were alive with the tumor recurrence and other nine patients were alive without recurrence. CONCLUSION: The management of the IVC after tumor resection depended on the tumor location and size. R0 resection provided a chance for long term survival.

LncRNA SNHG15 relieves hyperglycemia-induced endothelial dysfunction via increasing ubiquitination of thioredoxin-interacting protein.

OBJECTIVE: Numerous evidence indicates that hyperglycemia is a pivotal driver of the vascular complications of diabetes. However, the mechanisms of hyperglycemia-induced endothelial dysfunction in diabetes remain incompletely understood. This study aims to expound on the underlying mechanism of the endothelial dysfunction induced by hyperglycemia from the perspective of long non-coding RNAs (lncRNA). MATERIALS AND METHODS: Cell proliferation, migration, apoptosis, and tube formation were measured by cell counting kit-8 assay, transwell assay, flow cytometry, and tube formation assay, respectively. RNA pull-down and RNA-binding protein immunoprecipitation were used to detect the interaction between lncRNA SNHG15 and thioredoxin-interacting protein (TXNIP). Co-immunoprecipitation was used to detect the ubiquitination level of TXNIP and the interaction between TXNIP and E3 ubiquitin ligase ITCH. RESULTS: A downregulation of SNHG15 was observed in the ischemic hind limb of diabetic mice and high glucose (HG)-treated HUVECs. Functionally, the overexpression of SNHG15 promoted cell proliferation, migration, and tube formation, and suppressed cell apoptosis in HG-treated HUVECs. Mechanically, SNHG15 reduced TXNIP expression by enhancing ITCH-mediated ubiquitination of TXNIP. TXNIP overexpression abrogated the protective effect of LncRNA SNHG15 overexpression on HG-induced endothelial dysfunction. The following experiment further confirmed that SNHG15 overexpression promoted angiogenesis of the ischemic hind limb in diabetic mice. CONCLUSION: SNHG15 is a novel protector for hyperglycemia-induced endothelial dysfunction via decreasing TXNIP expression.

Hsa_circ_0008360 sponges miR-186-5p to target CCND2 to modulate high glucose-induced vascular endothelial dysfunction.

Vascular endothelial dysfunction is associated with the progress of many diseases. Circular RNAs (circRNAs) take part in the dysfunction of vascular endothelium. CircRNA hsa_circ_0008360 (circ_0008360) is dysregulated in high glucose-treated vascular endothelium, while the role and mechanism of circ_0008360 in high glucose-induced dysfunction remain unknown. Human umbilical vascular endothelium cells (HUVEC) were stimulated via high glucose. The abundances of circ_0008360, miR-186-5p and cyclin D2 (CCND2) were examined via quantitative real-time polymerase chain reaction or western blot. Vascular endothelial dysfunction was assessed via cell viability, apoptosis, migration and tube formation. The target relationship between miR-186-5p and circ_0008360 or CCND2 was analyzed via dual-luciferase reporter, RNA pull-down and RNA immunoprecipitation analyses. Circ_0008360 expression was enhanced in high-glucose-treated HUVEC. Circ_0008360 silence mitigated high glucose-induced suppression of viability, migration, tube formation, and increase in apoptosis in HUVEC. MiR-186-5p was sponged by circ_0008360, and miR-186-5p inhibition reversed the effect of circ_0008360 silence on high glucose-induced vascular endothelial dysfunction. MiR-186-5p alleviated high glucose-induced vascular endothelial dysfunction via targeting CCND2. CCND2 interference abolished the aggravated effect of circ_0008360 on high glucose-induced vascular endothelial dysfunction. Circ_0008360 knockdown attenuated high glucose-induced vascular endothelial dysfunction via regulating miR-186-5p and CCND2, indicating circ_0008360 might act as a target for the treatment of vascular endothelial dysfunction.Abbreviations: circRNAs, circular RNAs; HUVEC, human umbilical vascular endothelium cells; CCND2, cyclin D2; XPNPEP3, X-prolyl aminopeptidase 3; ceRNAs, competing endogenous RNAs; miRNAs, microRNAs; qRT-PCR, quantitative real-time polymerase chain reaction; RIP, RNA immunoprecipitation; HIF-1α, hypoxia inducible factor 1 alpha; TLR3, toll-like receptor 3; AKAP12, A-Kinase Anchoring Protein 12; ox-LDL, oxidized low-density lipoprotein; HG, high glucose; NG, normal glucose.

lncRNA KCNQ1OT1 Suppresses the Inflammation and Proliferation of Vascular Smooth Muscle Cells through IκBa in Intimal Hyperplasia.

Inflammation and proliferation of vascular smooth muscle cells (VSMCs) are the key events in intimal hyperplasia. This study aimed to explore the mechanism by which long non-coding RNA (lncRNA) KCNQ1OT1 affects VSMC inflammation and proliferation in this context. A vein graft (VG) model was established in mice to introduce intimal hyperplasia. Isolated normal VSMCs were induced with platelet-derived growth factor type BB (PDGF-BB), and the cell proliferation, migration, and secretion of inflammatory factors were determined. The results showed that KCNQ1OT1 was downregulated in the VSMCs from mice with intimal hyperplasia and in the PDGF-BB-treated VSMCs, and such downregulation of KCNQ1OT1 resulted from the increased methylation level in the KCNQ1OT1 promoter. Overexpressing KCNQ1OT1 suppressed PDFG-BB-induced VSMC proliferation, migration, and secretion of inflammatory factors. In VSMCs, KCNQ1OT1 bound to the nuclear transcription factor kappa Ba (IκBa) protein and increased the cellular IκBa level by reducing phosphorylation and promoting ubiquitination of the IκBa protein. Meanwhile, KCNQ1OT1 promoted the expression of IκBa by sponging miR-221. The effects of KCNQ1OT1 knockdown on promoting VSMC proliferation, migration, and secretion of inflammatory factors were abolished by IκBa overexpression. The roles of KCNQ1OT1 in reducing the intimal area and inhibiting IκBa expression were proved in the VG mouse model after KCNQ1OT1 overexpression. In conclusion, KCNQ1OT1 attenuated intimal hyperplasia by suppressing the inflammation and proliferation of VSMCs, in which the mechanism upregulated IκBa expression by binding to the IκBa protein and sponging miR-221.

[Establishment of a finite element model: canine segmental mandibular reconstruction by partial-cortical-cutting distraction osteogenesis].

OBJECTIVE: To establish a finite element model of canine segmental mandibular reconstruction by partial-cortical-cutting distraction osteogenesis. METHODS: The geometry model was established by Mimics software via reading the data of DICOM format from CT and was cut with Magics software. The finite element model was established and was analyzed by MARC software. RESULTS: A finite element model of canine segmental mandibular reconstruction by partial-cortical-cutting distraction osteogenesis was established. The model was composed of five parts. These five parts were felted via Magics software. The Von Mises stress of the joint region of slice and the slide segment were 34.60 MPa when the slide segment was retained 1.4 mm width during distraction osteogenesis with the force of 12 N. CONCLUSION: The biomechanics analysis can be complated through the finite element model of canine segmental mandibular reconstruction by distraction osteogenesis that retains lingual cortical bone.